title: Facile and efficient syntheses of a series of N-benzyl and N-biphenylmethyl substituted imidazole derivatives based on (E)-urocanic acid, as angiotensin II AT1 receptor blockers.
abstract: In the present work, a facile and efficient route for the synthesis of a series of N-substituted imidazole derivatives is described. Docking studies have revealed that N-substituted imidazole derivatives based on (E)-urocanic acid may be potential antihypertensive leads. Therefore, new AT1 receptor blockers bearing either the benzyl or the biphenylmethyl moiety at the N-1 or N-3 position, either the (E)-acrylate or the propanoate fragment and their related acids at the C-4 position as well as a halogen atom at the C-5 position of the imidazole ring, were synthesized. The newly synthesized analogues were evaluated for binding to human AT1 receptor. The biological results showed that this class of molecules possesses moderate or no activity, thus not always confirming high docking scores. Nonetheless, important conclusions can be derived for their molecular basis of their mode of action and help medicinal chemists to design and synthesize more potent ones. An aliphatic group as in losartan seems to be important for enhancing binding affinity and activity.
authors.affiliation: Department of Chemistry, University of Patras, Patras 26500, Greece. aggelisgeorge@hotmail.com
authors.forename: George
authors.initials: G
authors.lastname: Agelis
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Kelaidonis
authors.forename: Amalia
authors.initials: A
authors.lastname: Resvani
authors.forename: Dimitra
authors.initials: D
authors.lastname: Kalavrizioti
authors.forename: Maria-Eleni
authors.initials: ME
authors.lastname: Androutsou
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Plotas
authors.forename: Demetrios
authors.initials: D
authors.lastname: Vlahakos
authors.forename: Catherine
authors.initials: C
authors.lastname: Koukoulitsa
authors.forename: Theodore
authors.initials: T
authors.lastname: Tselios
authors.forename: Thomas
authors.initials: T
authors.lastname: Mavromoustakos
authors.forename: John
authors.initials: J
authors.lastname: Matsoukas
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D013329:Structure-Activity Relationship; D014560:Urocanic Acid / Q000737:chemistry / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D014560:Urocanic Acid